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4-Phenylbutyric acid regulates CCl4-induced acute hepatic dyslipidemia in a mouse model: A mechanism-based PK/PD
Hwa Young Lee1, Anu Marahatta1, Bidur Bhandary1
1Department of Pharmacology, School of Medicine, Chonbuk National University, Jeonju 560-182, South Korea.
Abstract:
Endoplasmic reticulum (ER) stress and associated protein aggregation are closely associated with human diseases, including alterations in hepatic lipid metabolism. Inhibition of ER stress can have a significant effect on the prevention of hepatic dyslipidemia. Here, we studied the role of 4-phenylbutyric acid (4-PBA), a chemical chaperone, on ER stress-induced hepatic lipid accumulation. We studied ER stress induction following CCl4 exposure and delineated mechanisms of the CCl4-induced ER stress response in liver tissue from mice. CCl4 affected the formation of disulfide bonds through excessive hyper-oxidation of protein disulfide isomerase (PDI). Increased complex formation between PDI and its client proteins persisted in CCl4-exposed samples. Conversely, 4-PBA inhibited ER stress via secretion of apolipoprotein B and prevention of hepatic lipid accumulation. We also studied the mechanism-based pharmacokinetic and pharmacodynamic profiles and identified the ER stress-related proteins GRP78 and CHOP, along with plasma apolipoprotein B and triglyceride levels, as novel biomarkers of ER stress-induced hepatic lipid accumulation. ER stress and its clinical relevance for therapeutic approaches were well correlated with the activity of the ER stress regulator 4-PBA, which may be a promising drug candidate for the treatment of hepatic lipid accumulation, such as hepatic steatosis.
Insights
4-phenylbutyric acid (4-PBA) reduces endoplasmic reticulum (ER) stress and hepatic lipid accumulation. This chemical chaperone shows promise for treating liver diseases like hepatic steatosis by improving lipid metabolism.
Area of Science:
- Biochemistry
- Cell Biology
- Hepatology
Background:
- Endoplasmic reticulum (ER) stress and protein aggregation are linked to human diseases, particularly affecting liver lipid metabolism.
- Inhibiting ER stress is crucial for preventing hepatic dyslipidemia.
Purpose of the Study:
- To investigate the role of 4-phenylbutyric acid (4-PBA) in mitigating ER stress-induced hepatic lipid accumulation.
- To elucidate the mechanisms underlying ER stress response in liver tissue following carbon tetrachloride (CCl4) exposure.
Main Methods:
- ER stress was induced using CCl4 in mouse liver tissue.
- The effect of 4-PBA on ER stress markers and lipid accumulation was assessed.
- Pharmacokinetic and pharmacodynamic profiles of 4-PBA were analyzed.
Main Results:
- CCl4 exposure led to excessive hyper-oxidation of protein disulfide isomerase (PDI) and increased PDI-client protein complexes.
- 4-PBA inhibited ER stress, enhanced apolipoprotein B secretion, and prevented hepatic lipid accumulation.
- GRP78, CHOP, plasma apolipoprotein B, and triglyceride levels were identified as biomarkers for ER stress-induced hepatic lipid accumulation.
Conclusions:
- 4-PBA effectively inhibits ER stress and prevents hepatic lipid accumulation.
- 4-PBA demonstrates potential as a therapeutic agent for hepatic steatosis and related lipid disorders.
- Identified biomarkers can aid in monitoring ER stress-related hepatic lipid accumulation.
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